1. Field of the Invention
The present invention relates to gene therapies for the treatment of heart diseases, particularly the enhanced delivery of polynucleotides to heart tissue.
2. Description of the Related Art
Heart disease is a major public health issue of very high prevalence, especially in the Western world. Cardiac conditions include coronary artery disease, ischemic heart disease, angina, heart failure, valvular heart disease, cardiac arrhythmias and cardiac inflammation (myocarditis) to name a few. Coronary artery disease and heart failure are possibly the most serious and prevalent, together being a leading cause of death in the Western world. The impact of acute myocardial infarction and congestive heart failure and their sequalae on the quality of life of patients and the cost of health care drives the search for new therapies.
Heart failure (HF) is a serious condition in which the heart loses its ability to pump blood efficiently. Data from the National Heart, Lung and Blood Institute, suggests about 5 million people in the United States alone have heart failure, and another 550,000 new cases are diagnosed each year. HF contributes to or causes about 300,000 deaths annually. The disease is most common in people aged 65 or older, women and African Americans. The most common symptoms of heart failure are shortness of breath, feeling tired, and swelling in the ankles, feet, legs, and sometimes the abdomen. There is no cure for congestive heart failure, and a clear need exists in the art for effective therapies.
One method of treating heart disease, such as HF, which has begun to receive more attention is gene therapy, wherein a polynucleotide is delivered to the cardiac tissue, typically in a viral vector. Numerous means of delivering viral vector to the heart have been attempted, including direct injection into the heart muscle (Liu et al., FASEB J. 2006; 20(2):207-16; Li et al. Toxicol. Appl. Pharmacol. 2006 Jan. 25 (electronic publication); Zhu et al., Circulation. 2005; 112(17):2650-9), intracoronary delivery (Nykanen et al., Circ. Res. 2006; 98(11):1373-80; Kaspar et al., J. Gene Med. 2005; 7(3):316-24), catheter-based antegrade intracoronary delivery with coronary venous blockade (Hayase et al., Am. J. Physiol. Heart Circ. Physiol. 2005; 288(6):H2995-3000), aortic and pulmonary artery cross clamping followed by proximal aortic injection of adeno-associated viral vector (Kaspar et al., J. Gene Med. 2005; 7(3):316-24). Leiden and Svensson mention in vivo infusion of a rAAV vector into a coronary artery or sinus generally, but only describe in detail the perfusion of a mouse heart with a reporter gene ex vivo at 4° C. where the heart has stopped beating (WO 00/38518)—a method that is impractical for the treatment of large mammals, such as humans.
Thus, these methods are all inadequate for use in a clinical setting, for example because these methods are too risky due to the need for surgical intervention or interruption of flow of oxygenated blood to the heart muscle, because of the amount of viral vector required to practice the method, because of the low percentage of tissue transfected, because the fact that transduction is limited to the site of the injection/administration only, or because the method is not practical or unproven for the treatment of disease in large animals or humans. There remains a need for a simple, minimally invasive, yet effective means of delivering transgenes using viral vectors to cardiac tissue to treat a disease, particularly in humans.
For instance, previously described in U.S. patent application Ser. No. 11/778,900 (incorporated herein by reference in its entirety) is a method of transfection of cardiac cells using a slow infusion of a therapeutic polynucleotide into coronary vessels. Increasing the efficiency of transfection of cardiac cells with the polynucleotide can lead to an increase in the efficacy of the treatment.
Use of nitroglycerin as part of a pretreatment cocktail has been used in myocardial gene transfer therapy in animals (see Sasano T., et al., “Targeted High-Efficiency, Homogenous Myocardial Gene Transfer” in J. Mol. Cell. Cardiol., 2007 May; 42(5):954-961, which is hereby incorporated by reference in its entirety, describes pig experiments involving myocardial gene transfer using a viral vector). In an effort to increase the efficiency of gene transfer in normal healthy pigs, they report using a pretreatment cocktail comprising vascular endothelial growth factor (VEGF), nitroglycerin, adenosine and calcium, followed by dosing with the viral vector and combinations of the above mentioned agents. However, their treatment protocols are not clinically practical as such protocols would lead to prohibitive hypotension and cardiac side-effects. For example, Sasano reports that “infusion of the pretreatment and virus solutions caused an immediate systolic blood pressure decrease of 30 mmHg that stabilized within the first minute of perfusion. The average heart rate also decreased to 50-60/min then stabilized over the same time course.” The authors reported further, “ventricular fibrillation (VF) occurred during coronary infusion in 5 of the first 10 pigs (50%) and 4 out of remaining 71 pigs (5.6%)” (Sasano et al. at pg. 958). Given the frail status of most human subjects with advanced cardiac disease, these side effects are likely even less tolerable than in young, normal, healthy animals.
Thus, there still exists a need to develop a treatment method for increasing the efficiency of cardiac transfection using vasodilation and viral vectors such as adeno-associated virus (AAV) that can be used in a clinical setting, without incurring life-threatening hypotension or cardiac arrhythmias.